Background: In postmenopausal women, estrogen biosynthesis takes place predominantly in adipose tissue through the catalyzed conversion from androgens by the aromatase enzyme. Variation in the CYP19A1 gene, which encodes the aromatase enzyme, is involved in the regulation of estrogen levels. Recent evidence also suggests that estrogen regulates several cancer-related adipocytokines including hepatocyte growth factor (HGF). HGF acts as an angiogenic growth factor in both an autocrine and paracrine fashion in various cell types to promote cell migration, proliferation, and invasion. It is plausible that the CYP19A1 gene which alters estrogen production also influences HGF concentrations. We accordingly conducted an evaluation of the CYP19A1 gene in relation to circulating HGF levels among postmenopausal women in the Women's Health Initiative Observational Study (WHI-OS).

Methods: We included in the present analysis a total of 45 CYP19A1 functional and common variants that were in Hardy-Weinberg equilibrium and had a minor allele frequency of ≥5%. As the distribution of HGF levels was highly skewed (p value for normality <0.001), we transformed HGF concentrations for all women into a log-, ranked-, or normal score (van der Waerden (VW) normal score method)-scale value. The associations between the CYP19A1 gene variants and the transformed HGF concentrations were assessed through a linear regression as implemented in PLINK with an additive scoring for 0, 1, or 2 copies of the minor allele of each variant. The analyzed models were adjusted for age (continuous) and body mass index (continuous). We also used linear regression to estimate haplotype-specific association with the rest of the haplotypes as the referents. To control for comparisons for multiple SNPs (or haplotypes), we performed 10,000 permutations to generate a gene-specific (familywise) empirical p value for each SNP (or haplotype) and to determine how frequently the identified association would occur by chance. We performed these permutations using the max(T) permutation option in PLINK.

Results: We observed an association between the rs7172156, rs1008805, rs6493494, rs749292, and rs11636639 variants and circulating HGF levels in ranked and normal score scales (corrected p values ≤0.04). Specifically, each additional copy of the minor allele of rs7172156 (T) and rs1008805 (C) was associated with lower mean HGF levels. By contrast, the minor alleles of rs6493494 (T), rs749292 (T), and rs11636639 (C) were each associated with higher HGF levels. These 5 SNPs, which were in linkage disequilibrium (pairwise D′ ≥97%, r2 ≥56%), collectively contributed ≥9% of total variance in ranked- and normal score-transformed HGF. Additionally, these 5 variants constituted block #6 of the CYP19A1 gene with 2 common haplotypes. One common haplotype (42%) containing the minor alleles of rs7172156 (T) and rs1008805 (C) was associated with lower HGF levels, whereas the other haplotype (40%) with the minor alleles of rs6493494 (T), rs749292 (T), and rs11636639 (C) was associated with higher HGF levels. The association of these 5 SNPs with log-scale HGF was not significant (corrected p values ≥0.17).

Conclusion: Our study suggests a potential association between the CYP19A1 gene variants and circulating HGF levels in ranked or normal score scales. However, our findings are exploratory and require confirmation in larger observational studies.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A67.